1. Field of the Invention
The present invention relates to a process for producing a 5-perfluoroalkyluracil (hereinafter referred to as RfU) which is useful as a medicine intermediate. More specifically, the present invention relates to an improved process for producing a 5-perfluoroalkyluracil comprising a first production step of reacting an .alpha.-perfluoroalkylacrylic acid (hereinafter referred to as RfAA) with a urea derivative to obtain a 5-perfluoroalkyl-5,6-dihydrouracil (hereinafter referred to as RfDHU), and a second production step of reacting the RfDHU with bromine to produce a 5-perfluoroalkyl-5-bromo-6-hydrouracil (hereinafter referred to as RfBrU). The RfBrU is thermally decomposable into RfU readily and quantitatively. RfU is the main source material for 5-perfluoroalkyluridines and derivative thereof which are important as medicines such as anticancer medicines, antiviral medicines, and antiherpes medicines.
2. Description of the Related Art
A process for producing a RfDHU is known which employs a perfluoroalkyl methyl ketone (C. Heiderberger, D. G. Parrsons and D. C. Remy: J.Med.Chem. 7, 1 (1964)). This process, however, comprises a larger number of production steps, and produces the product at an overall yield of as low as 7 to 16%.
JP-A-58-174371 discloses a process for producing 5-trifluoromethyl-5,6-dihydrouracil (herein after referred to as TFMDHU) starting from 2-halo-3,3,3-trifluoropropene. This process produces TFMDHU at a low yield, being not suitable for industrial production.
JP-B-61-48830 discloses a process for producing RfDHUs starting from RfAA and a urea derivative. This process requires an expensive condensing agent like dicyclohexylcarbodiimide, and complicated separating operation after the reaction, being not suitable for industrial production.
JP-A-60-19771 and JP-A-8-269020 discloses a process for producing RfDHUs by reacting RfAA with a urea derivative in the presence of acetic anhydride or a like carboxylic acid anhydride at a relatively high yield of from 65 to 70%. The inventors of the present invention replicated carefully the disclose processes to obtain a solid product, so-called TFMDHU, at an yield of about 75%. However, the obtained solid product of TFMDHU contained a large amount of acetyl urea as a byproduct as the result of precise analysis by the inventors of the present invention, and the actual TFMDHU yield was found to be as low as 42.7%.
JP-A-8-269020 discloses a process for purifying the produced TFMDHU in which the TFMDHU yield is improved to 70% at the molar ratio of RfAA to the urea derivative of from 1.0 to 1.5.
JP-A-61-254538 discloses a process of reacting 2-hydroxymethyl-3,3,3-trifluoropropionic acid with urea in the presence of acetic anhydride. This process involves longer reaction step, being not necessarily advantageous in view of the production cost and the overall yield.
On the other hand, as the second step, RfBrU can be produced by reaction of RfDHU and bromine. For example, in a known method, TFMDHU is reacted with bromine in acetic acid as the solvent (C. Heiderberger, et al.: J.Med.Chem. 7, 1 (1964)). This method requires a larger excess amount of bromine, two or more moles per mole of TFMDHU, and produces an irritating bromoacetic acids as a byproduct during the reaction process by bromination of the solvent acetic acid.
JP-A-60-94971 discloses a process of brominating a RfDHU with cupric bromide in a solvent containing a dialkyl carboxylic acid amide. This process gives a large amount of waste liquid after the reaction, and involves problems in operation and after-treatment.
JP-A-7-33750 discloses a process for producing 5-trifluoromethyluracil (hereinafter referred to as TFMU) by reacting RfDHU with halogen in an alkylsulfoxide in the presence of an acid catalyst in an alkylsulfoxide to produce 5-trifluoromethyl-5-halogeno-6-hydrouracil as the intermediate, and dehydrohalogenating the intermediate without isolating it. This process requires expensive iodine as the source material, and gives a large amount of waste liquid composed of the organic solvent containing the inorganic acid.
In either of the aforementioned JP-A-60-94971 or JP-A-7-33750, a purification process for the formed RfBrU is required: for example, recrystallization from ethanol or water, or extraction. Even with such purification step, a product of high purity cannot readily be produced.
The inventors of the present invention studied the process for producing an RfDHU as the first step by reacting RfAA with urea derivative in the presence of acetic anhydride. Consequently, the reaction was found to generates a great quantity of the reaction heat, when the source materials are charged together at one time, to render the reaction temperature uncontrollable industrially, resulting in low yield, disadvantageously as disclosed in JP-A-60-19771 and JP-A-8-269020. The heat of formation of the reaction product is estimated to be about 30 kcal/mol from the data in MOPAC (Ver.6) PM3, and Kagaku Binran [Kisohen II] (Chemical Handbook [Basic Data Collection II]).
Further, the inventors of the present invention studied the second step of the process for producing an RfBrU of high purity at a low cost.